JPH10287568A - Therapeutic agent for dipsomania - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a therapeutic agent for dipsomania tat has excellent amelioration of alcohol withdrawal symptoms by using a specific compound which has been appreciatingly used as a ameliorator for brain circulation. SOLUTION: This therapeutic agent for dipsomania contains ifenprodil or its pharmaceutically acceptable salt as an active ingredient. The agent is cased in the form of tablets, capsules, granules, fine particles, powder, syrup or injection solution. The daily dose of this active ingredient is orally 5-200 mg or 1-100 mg as an injection solution calculated as ifenprodil. The agent is excellent in effectiveness and safety without causing physical dependence and psychic dependence as the defects of conventional therapeutic agents.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic agent for alcoholism.

2. Description of the Related Art When a large amount of ethyl alcohol (ethanol) or foods and drinks containing ethyl alcohol (hereinafter, also simply referred to as "alcohol") is continuously consumed for a long period of time, biological functions are managed under the invasion of alcohol. The defense reaction of the living body that tries to maintain normality works, and finally a state in which the homeostasis of the living body does not work normally without the presence of alcohol, so-called alcohol dependence develops. When a patient with alcohol dependence stops drinking alcohol or the like, various psychosomatic symptoms accompanied by finger tremor and sweating appear several hours later. These various psychosomatic symptoms are regarded as symptoms that occur during the process of rapid reduction of alcohol from the blood, and in the past they were called alcohol withdrawal symptoms, but are now alcohol withdrawal symptoms or alcohol. Withdrawal symptoms (alcohol withdrawal sym
ptom) or alcohol withdrawal syndrome (alcohol withdrawal syndrome). The alcoholism referred to in the present specification is a concept that also includes such alcohol withdrawal syndrome or withdrawal syndrome and alcohol withdrawal symptom or withdrawal syndrome (hereinafter, sometimes simply referred to as “alcohol withdrawal syndrome”).

[0002] Alcohol withdrawal symptoms develop within a few hours after abstinence, and most often disappear within a few days to about ten days, but can vary from trivial to life-threatening.
Individual symptoms include finger / eyelid / body trunk tremor, sweating,
Autonomic nervous symptoms such as fever and tachycardia, hallucinations such as visual hallucinations, auditory hallucinations and hallucinations, seizures, tremor delirium (disorientation, hallucinations, illusions,
Confusion of consciousness accompanied by insomnia, anxiety, and psychomotor agitation, with the addition of coarse tremor, sweating, and other autonomic nervous symptoms)
and so on. The period during which these symptoms are observed is called the withdrawal period. In alcoholism, anxiety and sleep disorders may be observed even after the withdrawal period.

[0003] In the drug treatment of alcoholism,
In particular, since the treatment during the withdrawal phase in which the above-mentioned alcohol withdrawal symptoms have appeared is important, conventionally, in the withdrawal phase, a large amount of fluid replacement, glucose and vitamin for the management of the general condition.
While groups B and C are administered, withdrawal symptoms have been alleviated by administering a drug that has a cross physical dependence of the drug with alcohol. Drugs having such a cross-body dependence with alcohol include benzodiazepines and barbituric acid drugs.Specifically, diazepam, bromazepam, oxazepam and amobarbital are used. Diazepam is most often used. Although all of these physical dependence drugs are effective in alleviating or suppressing the symptoms of alcohol withdrawal, they are susceptible to physical dependence, such as diazepam, and at the same time cause mental dependence. When withdrawing from the drug, there is a risk that withdrawal symptoms may appear similar to or stronger than the withdrawal phase of alcohol, and it has not been entirely satisfactory as a therapeutic drug for alcohol dependence.

[0004] Ifenprodil used in the therapeutic agent of the present invention is currently used as an agent for improving cerebral circulation and metabolism, and has an α-receptor blocking effect on the sympathetic nervous system,
It is known that it has a vascular smooth muscle direct relaxing action, a platelet aggregation suppressing action, and the like. In addition, the neuroprotective effect of ifenprodil during cerebral ischemia in cerebrovascular disorders involves the antagonism of N-methyl-D-aspartate receptor (NMDA receptor) via a polyamine regulatory site. Known (Chemical Biological Medicine,
547-555, 1990; Ibid., 556-565, 1990). Furthermore, it has already been confirmed by Yanagiura et al. (Nihon Pharmaceutical Journal, 74 , 303-316, 1978) that ifenprodil has no ability to form physical dependence. Among these prior arts, ifenprodil has not been known at all to have any therapeutic effect on alcoholism.

[0005]

Problems to be Solved by the Invention / Means for Solving the Problems
The present inventors do not have the physical dependence and psychiatric dependence seen in conventional drugs for treating alcoholism, as a task to find a drug that improves the symptoms of alcohol withdrawal, as a result of examining various substances, Unexpectedly, it has been found that ifenprodil, which is currently awarded as a cerebral circulation metabolism improver, has an excellent ameliorating effect on alcohol withdrawal symptoms and is useful as a therapeutic drug for alcohol dependence. As a result of further research, the present invention has been completed.

[0006] The present invention relates to a therapeutic agent for alcohol dependence containing ifenprodil. Further, specific embodiments of the present invention include: (1) A therapeutic agent for alcohol dependence containing ifenprodil or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. (2) A form of the therapeutic agent is a tablet or a capsule. Preparations, granules,
The therapeutic agent for alcohol dependence according to the above (1), which is an oral preparation selected from the group consisting of fine granules, powders, and syrups. (3) The daily dose is 5 mg to 200 mg in terms of ifenprodil. (2) The therapeutic agent for alcohol dependence according to (2) (4) The therapeutic agent is an injection, and the therapeutic agent for alcohol dependence according to (1) above (5) The daily dose is 1 mg in terms of ifenprodil. The therapeutic agent for alcohol dependence according to the above (4), which is 〜100 mg.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention provides a therapeutic agent for alcohol dependence comprising ifenprodil or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. In the present invention, ifenprodil may be used as a free base or in the form of an acid addition salt thereof, which is pharmaceutically acceptable, that is, medically and pharmacologically usable as a medicament. The acid addition salt includes a non-toxic salt with an inorganic acid or an organic acid, and preferred inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and preferred organic acids include Acetic acid, lactic acid, tartaric acid, citric acid, fumaric acid, malic acid, maleic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid and
p-Toluenesulfonic acid and the like. This acid addition salt can be produced according to a method for producing an acid addition salt usually used in the field of organic chemistry.

[0008] The drug of the present invention comprises ifenprodil or an acid addition salt thereof alone or a pharmaceutically acceptable additive. Examples of the administration method of the drug of the present invention include a method by oral administration and parenteral administration, and are administered as an oral preparation and a parenteral preparation, respectively.
Oral administration is employed. In the case of this oral administration, the above-mentioned additive is a component as a pharmaceutical additive capable of constituting an oral preparation (hereinafter, also referred to as a “pharmaceutical component”) and can achieve the object of the present invention. Anything may be used, but usually excipients, binders, disintegrants,
Known formulation components such as lubricants and coating agents are selected. Specific oral preparations of the drug of the present invention include dosage forms such as tablets, capsules, granules, fine granules, powders, and syrups.

On the other hand, in the case of parenteral administration, specific examples include injections, suppositories, agents for mucosal or dermal administration, and in particular, in the case of injections, the above-mentioned additives include aqueous injections and non-injectable preparations. Pharmaceutical ingredients that can constitute an aqueous injection are used, and usually known pharmaceutical ingredients such as a solubilizer or a solubilizer, a suspending agent, a pH adjuster, and a stabilizer are used. It may be a well-known formulation component that constitutes a powder injection for use. In addition, additives for other parenteral administration agents may be any formulation components that are usually used for producing suppositories, ointments, creams, buccals, tapes and the like.

In order to obtain a desired oral preparation or injection by using the above-mentioned preparation components, a production method described in the 13th revised Japanese Pharmacopoeia (JP XIII) or an appropriate modification is added thereto. It can be manufactured by a manufacturing method. The dosage of ifenprodil and the acid addition salt thereof, which are the active ingredients of the drug of the present invention, is usually about 5 mg to 200 mg / day, preferably about 5 mg to 200 mg / day, when used as an oral preparation in terms of the amount of free base form of ifenprodil. 20mg-100m
g / day, and when used as an injection,
Usually, the dose is about 1 mg to 100 mg / day, preferably about 2 mg to 50 mg / day. In the case of parenteral administration other than injection, ifenprodil can be used in the same amount as that of an oral preparation. Specifically, the optimal dose is determined in consideration of the patient's duration of alcoholism, the severity of symptoms of alcohol withdrawal, the patient's age, sex, weight, and the like. Although the agent of the present invention may be used alone, it is of course possible to use it in combination with the above-mentioned existing drugs for treating alcoholism.

The drug of the present invention can be used particularly for the purpose of suppressing and improving the symptoms of alcohol withdrawal in humans, and is therefore effective for treating alcoholism. Ifenprodil used in the drug of the present invention has low toxicity and safety as can be understood from the fact that it has been used as a cerebral circulatory metabolism improving agent for patients with sequelae of cerebral infarction and sequelae of cerebral hemorrhage since 1978 in Japan. It is a compound with high. In addition, in the case of ifenprodil, the occurrence of physical dependence and psychiatric dependence, which have become major problems in conventional drugs for treating alcoholism, has not been a clinical problem at all. Hereinafter, the present invention will be described in more detail based on test examples and examples, but the present invention is not limited to these examples.

[Test Example] Test on the Inhibitory Effect of Ifenprodil on Alcohol Withdrawal <Test Method> In the test, male Fischer 344 rats were used. The feed is composed mainly of commercially available skim milk powder (Co-op skim milk, manufactured by Meiji Dairies) dissolved in tap water. Ethyl alcohol and white sugar (manufactured by Wako Pure Chemical Industries) are added, and the total calorie is always 875 kcal / 1000 ml. Was prepared as follows. The schedule for applying ethyl alcohol is Su
Zuki et al.'s method (General Pharmacology, 23 , 11-17, 199
According to 2), it was applied gradually for 26 days according to the schedule in Table 1. The rats were divided into four groups, and body weight and liquid feed intake were measured at 6:00 pm every day during the period of ethyl alcohol application. At 9:00 am on the final application day of ethyl alcohol, the liquid feed mixed with ethyl alcohol was replaced with ordinary liquid feed, the application of ethyl alcohol was stopped, the body weight was measured, and the method of Suzuki et al. (General Pharmacology, 23 , 11-1) was used.
7, 1992 and Life Science, 54 , PL 131-136, 1994). Ifenprodil (dose: 2.5, 5.0 and 10.0 mg / kg) is dissolved in physiological saline (solvent) containing 5% and 9% of dimethyl sulfoxide and polysorbate 80, respectively, and the application of ethyl alcohol is stopped for 3, 6 and 9 hours 30 of later observations
Minutes before each injection.

[0013]

[Table 1]

<Results> FIG. 1 shows the withdrawal symptom scores of the control group (the group not administered with ifenprodil; only the solvent was administered) and the group administered with ifenprodil after stopping the application of ethyl alcohol.

[0015]

FIG.

As can be understood from FIG. 1, when the application of ethyl alcohol was discontinued, severe withdrawal symptoms appeared at the peak of 9 hours after the discontinuation, and the withdrawal symptom score in the control group was 6 hours after discontinuation. 21.4 ± 2.3, and 28.8 ± 3.4 9 hours after discontinuation. On the other hand, in the ifenprodil 10 mg / kg administration group, the withdrawal symptom score was 6.9 ± 3.1 (p <0.01) at 6 hours after discontinuation, and 11.9 ± 1.6 (p <0.01) at 9 hours after discontinuation, significantly compared to the control group. Was suppressed. In the ifenprodil 5 mg / kg administration group,
The withdrawal symptom score was 14.3 ± 3.1 at 6 hours after discontinuation, which was a tendency to be suppressed compared to the control group, and at 9 hours after discontinuation, it was 19.2 ± 2.2 (p <0.05), which was significantly suppressed as compared to the control group. In the ifenprodil 2.5 mg / kg group, the withdrawal symptom score was 11.3 ± 6 hours after discontinuation.
2.2 (p <0.01), 16.7 ± 1.4 (p <0.01) 9 hours after discontinuation
And was significantly suppressed compared to the control group. From the above facts, it is understood that ifenprodil remarkably suppresses and improves the symptoms of alcohol withdrawal at the onset of alcohol dependence and is useful for the treatment of alcohol dependence.

[0017]

【Example】

[Example 1] Formulation example in one tablet (total amount 200 mg): ifenprodil tartrate 30 mg, crystalline cellulose 100 mg,
Lactose 48 mg, corn starch 20 mg and magnesium stearate 2 mg For the above formulation, tablets were prepared according to a known method described in the Japanese Pharmacopoeia (Japanese Pharmacopoeia XIII) General Rules for Preparations.

Example 2 Capsule Formulation in 1 Capsule (Total 150 mg): Ifenprodil Tartrate 20 mg,
Lactose 110 mg, corn starch 18 mg, and magnesium stearate 2 mg Capsules were prepared from the above formulation according to a known method described in the Japanese Pharmacopoeia (Japanese Pharmacopoeia XIII) General Rules for Preparations.

[Example 3] Formulation example in one ampoule of injection (2 ml in total): ifenprodil tartrate 5 mg, sodium chloride 2 mg, appropriate amount of known pH adjuster (adjusted to pH 6.5 to 7.5), methyl paraben 2 mg, water for injection Appropriate amount For the above formulation, an injection was prepared according to a known method described in the general rules of preparations in the Japanese Pharmacopoeia (JP XIII). [Example 4] Formulation in one suppository (total amount 2 g): ifenprodil tartrate 30 mg, witepsol (H-15) (manufactured by Dynamite Nobel) 1.97 g About the above formula, Japanese Pharmacopoeia (JP XIII) General rules of preparation Suppositories were prepared according to the known method described.

[0020]

EFFECT OF THE INVENTION The drug of the present invention has an excellent inhibitory / ameliorating effect on alcohol withdrawal symptoms of alcohol dependence without causing physical and mental dependence, which are the drawbacks of conventional drugs for alcohol dependence. It is a drug shown. Therefore, the present invention provides a therapeutic agent for alcohol dependence excellent in efficacy and safety.

[0021]

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the time course of the total score of alcohol withdrawal symptom when a rat whose alcohol application is stopped is administered with ifenprodil of the present invention.

Claims (5)

[Claims] 1. A therapeutic agent for alcohol dependence comprising ifenprodil or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 2. The therapeutic agent for alcohol dependence according to claim 1, wherein the form of the therapeutic agent is an oral preparation selected from the group consisting of tablets, capsules, granules, fine granules, powders, and syrups. 3. The therapeutic agent for alcohol dependence according to claim 2, wherein the daily dose is 5 mg to 200 mg in terms of ifenprodil. 4. The method of claim 1, wherein the form of the therapeutic agent is an injection.
The described alcohol dependence treatment agent 5. The therapeutic agent for alcohol dependence according to claim 4, wherein the daily dose is 1 mg to 100 mg in terms of ifenprodil.